Prior research indicates that smokers who metabolize nicotine more rapidly have lower quit rates in response to smoking cessation therapy. The rate of nicotine metabolism is one of the most robust predictors of abstinence. The overall goal of this proposal is to elucidate the as yet unknown mechanisms by which the rate of nicotine metabolism influences tobacco dependence. This could have important implications for understanding how particular smoking cessation medications work and in selecting the best medication for a particular smoker. Our studies will use the nicotine metabolite ratio (NMR) (the ratio between the nicotine metabolites 3'hydroxycotinine and cotinine, a test that was developed and validated by our laboratory) as a simple and clinically feasible biomarker for the rate of nicotine metabolism. We hypothesize that a faster rate of metabolism leads to faster elimination of nicotine from the body and a more rapid dissipation of brain tolerance to nicotine in the interval between cigarettes, leading in turn to (1) more severe nicotine withdrawal symptoms and (2) greater subjective reward from the cigarette smoked following deprivation. These effects would help to explain why smokers with faster rates of nicotine metabolism have a poorer response to smoking cessation therapy when compared to those with slower rates of metabolism. We will explore the relationship of the NMR to the endophenotypes of withdrawal, craving and reward, with the assumption that these factors are likely intermediaries for the mechanism linking nicotine metabolism to tobacco dependence and smoking cessation rates with pharmacotherapy. Our study design uses a brief (6 hour) interval of smoking abstinence followed by a reward cigarette to elicit the subjective responses relating to withdrawal and reward. Because smoking behavior and severity of nicotine dependence vary by race and sex we will also compare the relationship between NMR and withdrawal and reward in African American vs. white smokers and in men vs. women. Secondary analyses will examine whether nicotine half-life mediates the observed effects of NMR on primary response measures [additional aim relating to CYP2A6 genotyping has been eliminated]. PUBLIC HEALTH RELEVANCE: Nicotine dependence remains one of the major underlying causes of premature death and disability in our society. While the introduction of smoking cessation medications has increased quitting rates, absolute quit rates remain disappointingly low. The rate of nicotine metabolism, as assessed by the nicotine metabolite ratio (NMR) has been found in preliminary studies to be a robust predictor of smoking cessation in response to some types of medications. The mechanism by which the NMR predicts smoking cessation is not known, but could have important implications for understanding how particular smoking cessation medications work and in selecting the best medication for a particular smoker. The research described in this proposal will help elucidate the mechanisms by which the NMR is associated with nicotine dependence and the likelihood of quitting smoking, and may contribute to the development of personalized treatment strategies for smokers who want to quit.